A significant body of work implicates a vascular contribution to the pathogenesis of late-life depression. However, greater severity of cerebral hyperintense lesions, the hallmark of MRI-defined vascular depression, is not robustly associated with antidepressant outcomes. We propose that cerebral hypoperfusion, particularly in the frontal lobe, may be the underlying contributor to the clinical, cognitive, and radiological findings in late-life depression. The long-term goal of this line of research is to determine if frontal hypoperfusion is associated with antidepressant nonremission and, in future studies, to determine if pharmacological improvement of cerebral hypoperfusion may be a valid antidepressant augmentation strategy. The rationale for this project is that in older populations, cerebral hypoperfusion is often secondary to vascular disease, and in turn it may contribute to the development of depressive symptoms, cognitive deficits, and hyperintense lesions. Although antidepressants may improve regional perfusion, it is unclear if they do so in individuals with hypoperfusion related to systemic vascular disease. Such individuals may be antidepressant-resistant but could receive benefit from approaches that improve cerebral perfusion. As the first step in this line of research, the objective of the current proposal is to determine if frontal hypoperfusion in depressed elders predicts and persists with antidepressant nonremission. We will pursue our primary aims which will test our hypothesis that frontal hypoperfusion, specifically in the dorsolateral prefrontal cortex and dorsal anterior cingulate cortex, will predit antidepressant nonremission. Additionally, we predict that antidepressant remitters will show increased frontal perfusion with treatment while nonremitters will see no significant improvement in frontal perfusion with antidepressant treatment. Our approach is to enroll 40 depressed elders who will complete clinical, cognitive, and MRI assessments before and after a 12-week open-label antidepressant trial of sertraline. Regional cerebral perfusion will be assessed pre- and post-treatment using arterial spin labeling (ASL) at rest and during an emotional oddball task. This will allow us to examine if reduced frontal perfusion is predictive of and persists with antidepressant nonremission. This proposal is innovative as it builds on but moves beyond the vascular depression hypothesis to examine mechanistically how cerebral perfusion influences late-life depression and antidepressant outcomes. It is additionally significant as it will improve our understanding of the pathogenesis of late-life depression and, if our hypotheses are correct, provide an opportunity to test the antidepressant properties of commercially available drugs which improve cerebral perfusion.